Effect of 6-Month HIV Preexposure Prophylaxis Dispensing With Interim Self-testing on Preexposure Prophylaxis Continuation at 12 Months

Key Points Question Does 6-month daily oral HIV preexposure prophylaxis (PrEP) dispensing supported with interim HIV self-testing reduce the number of annual PrEP clinic visits without jeopardizing client continuation outcomes at 12 months? Findings In a randomized noninferiority trial among 495 adults in Kenya, semiannual PrEP dispensing supported with interim HIV self-testing resulted in noninferior HIV testing and PrEP adherence 1 year after initiation compared with standard quarterly PrEP dispensing. Meaning The findings of this study suggest that this differentiated model of PrEP service delivery could simplify and optimize PrEP delivery.

Maximizing access and minimizing costs of delivery are key challenges for optimizing the public health impact of 206 pre-exposure prophylaxis (PrEP) for HIV-1 prevention, particularly for resource-constrained settings. PrEP is 207 highly effective and safe when taken as prescribed, and demonstration studies are showing how PrEP can be 208 delivered in clinical settings. In Africa, PrEP will be added to an already-burdened health infrastructure and the 209 ability of public health systems to afford PrEP will necessitate making its delivery cost-effective and time-efficient.

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PrEP delivery programs will need to be cost-sensitive to staffing needs (e.g., frequent clinic visits); moreover, 211 patients may not continue PrEP if their costs (e.g., travel to / waiting in clinics) are high. HIV-1 testing is central to

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PrEP: testing must occur prior to initiation and ongoing HIV-1 testing is essential for delivery. Like PrEP, HIV-1 213 self-testing is a recent innovation and its opportunities to improve HIV-1 prevention have not been fully realized.

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We hypothesize that HIV-1 self-testing can streamline PrEP delivery -through decreasing the frequency of PrEP

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Follow-up: PrEP refills will occur at clinic visits -quarterly (standard of care) and 6-monthly (self-238 testing), outcomes will be measured at Months 6 and 12. Outcomes: PrEP adherence (defined by 239 PrEP quantity in dried blood spots and persistence in refilling PrEP), HIV-1 testing, and safety 240 (including side effects and social harm).

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Aim 2: We will conduct mixed-methods work to understand user and provider experiences, 243 preferences, barriers, and facilitators related to HIV-1 self-testing.

Hypothesis:
HIV-1 self-testing will appeal to patients, because of greater self-efficacy and reduced opportunity 245 costs, and providers, for reduced workload. Blood-based tests may inspire greater confidence than 246 oral fluid tests. Gender and partner involvement may influence acceptability of HIV-1 self-testing.

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Approach: Triangulating data from structured survey and qualitative interviews, we will assess patient and 248 provider perceived benefits of and concerns about HIV-1 self-testing in the context of PrEP.

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Aim 3: We will assess costs and cost-effectiveness of HIV-1 self-testing to optimize PrEP delivery.

Hypothesis:
HIV-1 self-testing will decrease the cost of PrEP delivery and improve PrEP cost-effectiveness.
of PrEP's efficacy for HIV-1 protection -explained by the degree to which the trial populations were adherent to PrEP [9] . Secondary analyses from clinical trials and demonstration studies have shown that PrEP is clearly men, and young women at risk for HIV-1 than in prior clinical trials [12][13][14] , which has been hypothesized to be a 295 result of offering a strategy with demonstrated safety and effectiveness, and without a placebo. In those PrEP 296 demonstration studies, HIV-1 incidence has been low and visits were generally quarterly and brief, suggesting that 297 many who initiate PrEP in the context of known safety and efficacy may not need frequent or intensive follow-up to 298 achieve high adherence.

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Strategies to effectively and efficiently deliver PrEP are needed

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PrEP delivery can be expensive, in terms of medication costs, staffing time, laboratory testing, and patient 304 opportunity costs. Multiple analyses from high-income settings have argued that, while PrEP is cost-effective when 305 delivered to high-risk persons, it is still a costly intervention [15][16][17] . For developing country settings, the results are 306 similar -even when taking into account lower cost inputs such as generic or discounted medication pricing, lower 307 staff salary costs, and more truncated laboratory testing recommended by WHO and country policies [16,18] . Thus, 308 costs will be a barrier to PrEP delivery for impact, in all settings.
In costing analyses we have conducted in East Africa, we estimated that adding PrEP to routine public health services using Ministry of Health personnel, drug, and laboratory costs would cost ~US$100 annually per person.
personnel (39%) [19] . That finding emphasizes the need for efficiency in PrEP delivery, particularly so given that 314 qualified medical staff in Kenya and similar settings are often highly over-stretched, because of competing priorities 315 in overburdened health systems. Our modeling did not take into account patient costs related to PrEP; however, we 316 have learned through providing PrEP in studies to over 5000 individuals over the past 10 years that travel and time 317 away from work and costs for getting to PrEP clinic visits can be a challenge for persons taking PrEP. Efficient 318 strategies to deliver PrEP could reduce costs, potentially improving patient engagement and allow services to be 319 available to a larger number of people as a result -and this kind of approach would be applicable in a variety of 320 settings worldwide.

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HIV-1 testing is central to PrEP; HIV-1 self-testing is a novel approach that could streamline PrEP delivery

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Point-of-care HIV-1 testing is a standard component of PrEP delivery.

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PrEP requires regular HIV-1 testing -at the time of PrEP initiation and then in an ongoing basis.  HIV-1 testing [2] . Ongoing projects, some at very large scale [25,26] , are evaluating wide-scale distribution of HIV-1 361 self-tests in Africa. WHO now recommends HIV-1 self-testing as an additional testing option for individuals and 362 countries [27] .

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No studies have put HIV-1 self-testing and PrEP together.

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Evaluating HIV-1 self-testing within a PrEP context has not been evaluated, although our pilot work (detailed 367 below) suggested both feasibility and acceptability. In the present study, we propose that HIV-1 self-testing can reduce facility-based periodical testing and clinics visits among persons receiving PrEP and can do so safely and 369 without detrimentally affecting adherence. Our proposed model has several potential advantages. First, self-testing 370 could provide an efficient method that achieves the objectives of achieving high adherence to PrEP and ensuring Second, both PrEP and self-testing are new and seeing how they fit together is an incredible new opportunity. Third, efficiency of delivery could be appealing not only to the policy makers (reduced cost) and health providers (reduced work load) but also to the PrEP users (reduced clinic visits).

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Summary: unanswered questions and central hypothesis

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For persons taking PrEP for HIV-1 prevention, regular HIV-1 testing at fixed-site clinics has been the standard. We hypothesize that HIV-1 self-testing can replace some of the periodic follow-up HIV-1 testing otherwise done at a 380 facility for persons receiving PrEP, reducing clinic and patient burdens. As detailed below, the proposed work will 381 build on and extend our prior work in PrEP and HIV-1 self-testing, by proposing a novel model of delivering PrEP 382 through fewer clinic visits which has the potential to revolutionize PrEP delivery.

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The Government of Kenya has proposed a visionary 20-year plan for evidence-based HIV-1 prevention,

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We have conducted randomized trials, behavioral science, implementation science, and mathematical modeling to 445 define the efficacy, acceptability, and cost-effectiveness of PrEP for HIV-1 prevention.

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PrEP is effective and safe for prevention

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We conducted the Partners PrEP Study, the randomized clinical trial that demonstrated the efficacy of PrEP for

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HIV-1 prevention in heterosexual populations [4,32] . Secondary analyses from that trial confirmed that PrEP 451 provided significant protection including in key subgroups: both men and women [33] , couples with high-risk 452 characteristics (e.g., those practicing unprotected sex, couples in which the HIV-1 infected partner had a high 453 plasma viral load, those with sexually transmitted infections) [33] , and in women using contraception [34] . We also 454 conducted analyses to demonstrate limited selection of antiretroviral resistance [21] , safety in women using 455 contraception or who become pregnant [35,36] , and limited renal toxicity [37][38][39] . Our work has been central to the 456 development of PrEP guidance for populations worldwide [40,41] .

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We conducted a large-scale demonstration of integrated ART and PrEP that showed near-elimination of compared to 83 in a simulated counterfactual cohort (Figure 1).

Pilot study: HIV-1 self-testing is highly acceptable in the context of PrEP. Within the Partners Demonstration
test kits were provided for use, at home, in the two-month interval between scheduled quarterly clinic visits. We testing kit was easy. Many reported that HIV-1 self-testing was empowering (

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Costing studies and cost-effectiveness modeling.

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We have extensive experience with cost and cost-effectiveness studies to understand the deliverability of prevention

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Taking PrEP to scale will require simplifying models for delivery, for cost savings and patient preference. We have 523 assembled a multidisciplinary team to test a simplifying strategy for PrEP delivery. We hypothesize that alternating 524 home HIV-1 self-testing with clinic based HIV-1 testing -with resulting reductions in clinic visits from quarterly to 525 semiannually -will translate into cost savings for PrEP programs as well as patient related opportunity costs, 526 without reducing PrEP adherence, and will be feasible, acceptable, preferred, and safe.

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Aim 1: In a randomized trial, we will test the use of HIV-1 self-testing to decrease the frequency and 531 burden of clinic visits for PrEP while resulting in equivalent adherence and testing.

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Hypothesis. Global guidelines recommend HIV-1 testing quarterly for persons on PrEP; we propose that HIV-1 534 self-testing could alternate (e.g., Months 3, 9) with clinic-based testing (e.g., Months 6, 12) to cut the frequency of 535 clinic visits in half, saving staffing and patient costs, without reducing PrEP adherence or persistence.

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Aim 2: We will conduct mixed-methods work to understand user and provider experiences, 538 preferences, barriers, and facilitators related to HIV-1 self-testing.

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Hypothesis. HIV-1 self-testing will appeal to patients, because of greater self-efficacy and reduced opportunity 541 costs, and providers, for reduced workload. Blood-based tests may inspire greater confidence. Understanding for 542 whom self-testing "works" will help define differentiated care models for PrEP delivery.

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Aim 3: Assess the cost and cost-effectiveness of HIV-1 self-testing to optimize PrEP delivery.

Hypothesis.
HIV-1 self-testing will decrease the cost of PrEP delivery and improve PrEP cost-effectiveness,

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allowing for greater efficiency, reach, and impact.

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Population 550 551 At the Thika clinic, we will recruit women and men in HIV-1 serodiscordant relationships (n=165 HIV-1 uninfected 552 women and n=165 HIV-1 uninfected men) and HIV-1 uninfected women at risk (n=165) who have recently initiated

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PrEP for this project. We will aim to have equal enrollment for the three study groups, but will over-enroll HIV-1 554 uninifected women at risk if we have difficulties or delays in enrolling men or women in HIV-1 serodiscordant 555 relationships, whom historically have been more difficult to enroll.

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Standard HIV-1 testing arm 560 Participants will receive baseline and quarterly HIV-1 counseling, condoms, risk reduction counseling, and 561 syndromic management of sexually transmitted infections according to local guidelines.

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Participants will receive baseline and semiannual HIV-1 counseling, condoms, risk reduction counseling, and 565 syndromic management of sexually transmitted infections according to local guidelines.

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Both study arms

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To ensure as real world assessment of uptake and sustained use of PrEP as possible, tracing of participants will 569 occur only for follow-up of safety issues and for HIV-1 assessment, but not for completion of routine visits and    States. The World Health Organization recommends TDF-containing medications as PrEP, which includes TDF 611 combined with FTC as well as potentially TDF alone and TDF combined with lamivudine (or 3TC, a medication 612 closely related to FTC). Any TDF-containing medications that align with WHO and Kenya national guidelines for PrEP will be used in this study. PrEP will be prescribed for once-daily use. Study medication will be provided 614 by the Kenya Ministry of Health.

616
The study drug will be stored in accordance with the drug manufacturer's recommendations. The pharmacy and storage facility will have locked, climate-controlled environments, with controlled humidity and temperature to remain within limits allowed by the manufacturer for drug storage. Dispensing will be sufficient to last until the next visit -thus, at enrollment month, a three month and six monthly supply depending on the study arm.

621
Counseling on the medications being used, their side effect profiles, how to take the study medication, what to do if 622 side effects are experienced, and the importance of not sharing study medication to optimize potential efficacy and 623 to reduce the chances of developing resistance through suboptimal HIV-1 suppression if study medication is shared 624 with others.

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The OraQuick In-Home HIV Test (Figure 2)  and is categorized as a "screening" test, therefore a second 637 test to confirm the results is recommended.

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The

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If there are any issues or interruptions with the procurement of AtomoRapid HIV self-testing kits in country, we will 660 procure and train participants on the use of other HIV self-testing kits that have been prequalified by the WHO, an 661 official observer of the International Medical Device Regulators Forum. We will ensure that all HIV self-testing kits 662 utilized by participants in this study will have a greater than 95% sensitivity and specificity. A list of applicable HIV 663 self-testing kits is available in the UNITAID's HIV Rapid Diagnostic Tests for Self-Testing, 4 th Edition. [45] 664 665

667
The Thika site has established local recruitment and screening methods that operationalize protocol-specified 668 requirements for eligibility determination in a manner that is tailored to and most efficient for the local study setting 669 and target study population.

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Thika is an urban center, about 40 km outside of Nairobi, and has a large peri-urban and rural population base Those randomized to self-testing will be further randomly assigned to half receive oral-fluid tests and half bloodget 6 months of PrEP medication at each visit while only those on the clinic based arm will get 3 months of PrEP, corresponding to enough to last until the next clinic-based visit. Participants in both arms will be counseled on PrEP 730 discontinuation according to Kenya national guidelines (e.g., for HIV-1 uninfected members of HIV-1 731 serodiscordant couples, 6 months after their partner has begun taking ART, if there are no other HIV-1 risks).

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Tracing for retention at Months 6 and 12 will be done, particularly to establish PrEP continuation and HIV-1 status.

733
All HIV-1 serodiscordant couples will receive counseling on PrEP as a bridge to ART; infected partners will be 734 encouraged to start ART if not already started (Tables 2-4).

736
As we did in our pilot evaluation (detailed above) those assigned to self-testing will receive training -blood or oral 737 depending on their assignment and will complete one test in clinic on the day of randomization including 738 interpretation of the test result under the guidance of the study staff to increase comfort with the process. Those 739 assigned to HIV-1 self-testing will be provided with two self-testing kits to conduct quarterly testing until their next 740 scheduled visit (i.e., one test kit for the quarterly visit and an extra kit to be used as back-up), and participants will 741 be counseled to use the self-testing kit at a place and time where they will feel comfortable performing the testing 742 (e.g., at home). Participants will also be asked to bring back the used HIV-1 self-test kits to confirm HIV-1 self-743 testing (though this method has limitations, it will be a proxy measure). As we did for our pilot study, a pictorial 744 information brochure translated into local languages will be provided and a toll-free 24-hour helpline will be 745 provided to call in case of challenges in performing the self-testing or in the event of a positive test result.

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Participants will be informed that any positive self-test result will need to be confirmed by study staff in accordance

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At the final visit (Month 12, for most participants) all participants will be trained on a HIV-1 self-testing method 752 that they had not used and offered an opportunity to self test using the new method, specifically those on the 753 standard arm will be trained on both oral HIV self-testing and blood based HIV self-testing while those on the oral

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HIV-1 self-testing arm will be trained on the blood based HIV self-testing and those on the blood based HIV-1 self-755 testing will be trained on the oral HIV-1 self-testing. A HIV-1 testing preference questionnaire will then be 756 administered to assses participants preferences between the three HIV-1 testing methods.

758
At each study visit, we will offer counseling for participants for HIV-1 testing (pre-and post-testing), HIV-1 759 infection risk reduction best practices, condom promotion and provision, adherence to HIV-1 medication, adherence 760 to HIV-1 self-testing, and PrEP and ART as HIV-1 prevention strategies.   Seroconversion will be determined by local HIV-1 testing guidelines. For initially HIV-1 uninfected participants 825 who seroconvert, a plasma sample or dried blood spot will be collected and archived for tenofovir levels and 826 resistance testing. Couples and young women in which the initially HIV-1 uninfected participant seroconverts will 827 be exited from the study but will continue with their normal HIV clinic care follow up as usual. A suspected 828 seroconversion will be confirmed per the Kenyan National Testing Algorithm. In addition, suspected seroconverters 829 will have a blood sample drawn that will be sent to laboratory identified by NASCOP for drug resistance testing as

841
Participants may voluntarily withdraw from the study for any reason at any time. The site Investigator also may 842 withdraw participants from the study in order to protect their safety and/or if they are unwilling or unable to comply 843 with required study procedures. Reasons for withdrawal will be recorded.

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High adherence is important for PrEP effectiveness in preventing HIV-1 acquisition. Study staff also will provide 848 brief adherence counseling at each scheduled visit, in accordance with Kenya PrEP counseling guidelines.

850
Data on adherence to the product use regimen will be collected via standardized interviewer-administered questions 851 to ascertain product use. Finally, adherence will also be assessed through batched drug levels at enrollment and 852 study visits at Months 6 and 12. Dried blood spots and plasma from batched drug levels will be shipped to the 853 University of Washington for processing and analysis for tenofovir drug levels. Dried blood spot data are improved 854 when analyzed with standardization against hemoglobin concentrations.

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PrEP continuation will be according to Kenya PrEP guidelines. Use of PrEP may be interrupted by the site

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Investigator due to safety concerns for the participant, use of concomitant medications that could interfere with PrEP 860 or present a safety concern, or if the participant is unable or unwilling to comply with study procedures. All 861 treatment interruptions will be documented. Uganda. There were no statistically significant differences in the frequency of deaths, serious adverse events, adverse events overall, or key laboratory adverse events (specifically, creatinine elevation and phosphorus decrease)

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for those receiving PrEP compared to those receiving placebo in the Partners PrEP study.

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For the purposes of this study, only serious adverse events (SAEs), for both index (HIV-1 infected) and partner (HIV-1 uninfected) participants, and adverse events felt related to PrEP or self-testing will be documented. SAEs 877 felt to be related to PrEP will result in temporary hold of PrEP. In the case of temporary holds, the hold will 878 continue until the event is stabilized or resolved. If the event resolves, PrEP may be reinitiated at the discretion of 879 the Investigator, resuming safety monitoring. The severity of clinical symptoms will be scored using the DAIDS

902
For the self-testing arms, there is an inherent difference in sensitivity between the oral fluid-and blood-based tests,

903
as detailed above; we recognize this as a potential risk for undetected infection, and ascertainment of the magnitude 904 of that risk will be part of this evaluation. Incident HIV-1 infections are rare among persons offered PrEP (<0.5%

905
per year in our prior work, and essentially 0% among those taking PrEP) and thus HIV-1 acquisition is expected to 906 be very uncommon in this study.

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We have extensively considered the risk of social harm related to both PrEP use and HIV-1 self-testing at home, including risks of depression/anxiety and disclosure and stigma. Our extensive experience with longitudinal follow-912 up of heterosexual HIV-1 serodiscordant couples and women at risk mitigates some of this risk, and we found very 913 little risk of social harms or anxiety related to HIV-1 self-testing in our pilot evaluation, among couples (detailed 914 above). Low evidence of social harms has been reported in other HIV-1 self-testing studies [47] . The 24-hour 915 helpline that that Thika clinic has, and which we used for our pilot study, will be available in case of anxiety, social 916 harm, depression, or a positive test. Analyses of social harm related to self-testing will be done overall, by sex and by relationship status, given the potential for differential gendered and relationship risks (detailed more in Aim 2).
In the event of a clinical need (e.g., side effects, symptoms of a sexually transmitted infection), participants will be requested to return to the clinic for care.

925
The primary goal of this project is to address key access and cost of delivery challenges for PrEP by using the new 926 modality of HIV-1 self-testing.

928
Data collection

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We will use structured interviews on HIV-1 testing practices and self-reported PrEP adherence (e.g., frequency, 931 ability, self-rating, missed doses). We will use CommCare, an electronic data capture platform, to collect data at the 932 Thika site.

934
Qualitative data collection

936
Qualitative data collection will include serial in-depth interviews using pre-piloted semi-structured guides (n=20 937 men in couples, n=20 women in couples, and n=20 women at risk, from both self-testing modalities and the standard taker.The semi-structured qualitative interview guide will provide a general structure for discussion but require 941 participants to share their own barriers and facilitators [48] . The serial in-depth interviews will be conducted soon

949 950
Qualitative discussions will be recorded, transcribed, and translated into English by the study team. Audio 951 recordings will be destroyed by the qualitative team after being transcribed not later than August 2023. Qualitative 952 work will extend our prior work among couples and women at risk, and we will adapt existing questionnaires and 953 topic guides to focus on questions related to HIV-1 testing in the context of PrEP delivery, specifically to gain a 954 deeper understanding of participants' experiences with HIV-1 self-testing, including challenges, benefits, concerns, 955 risks, preferences (self-versus provider-based testing) and intention to use in the future, if available.

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Health provider barriers and facilitators to HIV-1 self-testing

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Health providers are key to PrEP delivery [49] . Therefore, in addition to self-testing users, we will study operational 960 delivery at the level of providers. We will conduct key informant interviews (n=6-8) with providers at the research 961 clinic (counselors, nurses, clinicians) to understand acceptance, barriers, facilitators, and confidence regarding HIV-962 1 self-testing in the context of PrEP. Interviews will be conducted at the end of the study. We will document 963 suggestions on how to optimize PrEP delivery through the use of HIV-1 self-testing. We will use similar interview 964 and analysis methods detailed above.

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Trial outcomes will be PrEP adherence (PrEP quantity in dried blood spots and PrEP refills), HIV-1 testing 969 completion, and safety (including accuracy of HIV-1 testing, management of side effects, and social harm).

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Timing. All outcomes will be assessed at the Month 6 and 12 clinic visits. The study is powered against a single which has become the gold standard for research evaluations of PrEP adherence [10,11] . High TFV-DP levels will define good adherence. In recent studies, levels ≥1250 fmol/punch (=the median among persons taking 7 doses/week) and ≥700 (=≥4 doses/week, associated with high HIV-1 protection in some studies) have been used. levels of hemoglobin, which has been validated as a more accurate means of interpretating drug levels.PrEP refills explore potential differences in acceptability and cost between self-testing modalities. Power. The trial will be powered for the adherence outcome (measured by detection of PrEP in dried blood spots). Based on our prior work in couples, and published work for women at risk, we estimate ~80% among those seeking to initiate PrEP will achieve blood levels consistent with high PrEP adherence [51,52] . Thus, if PrEP adherence is 80% in both the standard of care and self-testing arms, with 80% power, 10% loss-to-follow-up, a one-sided 95% confidence interval (common for non-inferiority trials), and a 10% non-inferiority margin, a sample size of n=495 is needed (n=330 self-testing, n=165 standard of care). A 10% non-inferiority margin has been chosen as an important reduction in planned for two sub-analyses with sample sizes of n=330: those in HIV-1 serodiscordant relationships (which will include 165 men and 165 women) and women (which will include the 165 in serodiscordant relationships pus an additional 165 women at risk). These primary sub-analyses will have 80% power to rule out a 12% decrease in adherence (i.e., a slightly greater non-inferiority margin). We have considered whether enrolling n=330 women at risk (rather than n=165, alone or in addition to n=330 couples) would be warranted but feel we can gain important information about both of these populations through the hybrid design, with greater efficiency, in time and in costs.
However, we recognize that women outside of serodiscordant relationships may face unique adherence challenges 1021 and less frequent follow-up could be truly inferior to quarterly follow-up; thus, among the n=165 women at risk, we will also plan a superiority analysis, for which we will have 80% power to detect a decline in adherence from 80% 1023 to 66% (14% lower) with self-testing. For the HIV-1 testing outcome, utilization of self-test kits will be compared between arms; assuming 95% of participants test, we have 80% power to detect a difference of 5% in use of consistent use of self-testing kits (90% vs. 95%). Also, if we end up having to over-enroll HIV-1 uninfected women at HIV-1 risk not in disclosed HIV-1 serodiscordant relationships to compensate for difficulties or delays in enrolling HIV-1 uninfected men and women in HIV-1 serodiscordant relationships, we will have more power to detect outcomes in this important sub-group.
Costing. The costs for a PrEP delivery program that uses HIV-1 self-testing with 6-monthly visits compared to 1032 quarterly visits with standard testing will be estimated. Activity-based micro-costing will be conducted and 1033 compared by study arm for costs incurred (start-up activities, recruitment, service delivery, monitoring costs, and 1034 adherence support) and costs averted (personnel, lab monitoring, incident HIV-1 cases, social, and health benefits).

1035
Time and motion studies will be conducted by observing clinic visits, and staff time spent on training on use of 1036 home HIV-1 self-testing, counseling clinical procedures, cost of the three types of HIV-1 self-testing kits (blood 1037 based provider kit, blood based HIV-1 self-testing kit and oral based HIV-1 self-testing kit) and ART and PrEP 1038 delivery. Adjusting for time spent on research activities (e.g., informed consent, research questionnaires), the total 1039 time required for PrEP delivery will be estimated. Estimates of cost using the activity-based approach will be 1040 compared with the top down (dividing the budget by the number of clients) approach to support scalable estimates 1041 of cost. Costs incurred by clients for clinic visits (which contribute to the societal perspective) will be estimated 1042 with standard questionnaires that we have used previously.

1044 1045
Model. Mathematical models will be used to simulate health outcomes from a combination of study data and the 1046 literature, allowing us to consider clinical outcomes beyond the scope of the prospective cohort. We will adapt our individual-based HIV-1 model to include PrEP [55] . Assumptions will be as published previously, including our 1055 publication on micro-costing work within the Partners Demonstration Project [19] .

1056
For key delivery informants

1058
Health providers are key to PrEP delivery [49] . Therefore, in addition to self-testing users, we will study operational 1059 delivery at the level of providers. We will conduct key informant interviews (n=6-8) with healthcare providers at the 1060 research clinic (counselors, nurses, clinicians) to understand acceptance, barriers, facilitators, and confidence 1061 regarding HIV-1 self-testing in the context of PrEP. Interviews will be conducted at the end of the study. We will 1062 document suggestions on how to optimize PrEP delivery through the use of HIV-1 self-testing. We will use similar 1063 interview and analysis methods detailed above.

1068
Analyses will be intention-to-treat. HIV-1 testing and PrEP detection in blood will be compared between arms 1069 using repeated measures analysis of proportions (e.g., generalized estimating equations [GEE]); PrEP continuation, 1070 defined as not missing any refill, will be analyzed as a time-to-event outcome using Cox proportional hazards 1071 regression. As noted above, for the couples, those in which the HIV-1 uninfected partner completes PrEP use 1072 because the infected partner has initiated and sustained ART for >6 months (the Kenya standard for discontinuing 1073 PrEP) will be considered to have successfully used PrEP and will be counted as adherent; similarly, if PrEP is 1074 discontinued by the treating clinician for safety reasons (but not adherence reasons), follow-up thereafter will be 1075 censored, since the subject will not be able to be assessed for adherence to PrEP. Adjusted analyses will be done as 1076 needed, controlling for potential confounders based on our prior work assessing correlates of PrEP use: 1077 demographics (e.g., gender, age, educational level), sexual behaviors (e.g., condom use, outside partnerships), 1078 medical status (e.g., depression), and beliefs (e.g., risk perception, PrEP efficacy). SAS or R will be used.

1080
For quantitative data, descriptive analyses will be done at baseline and over time, and GEE will be used to test 1081 associations between facilitators/barriers and testing preferences outcomes. Analyses will be done to test effect 1082 modification by gender and, within women, by serodiscordant couple status

Qualitative Analysis
The transcripts will be reviewed separately by two investigators for completeness and initial theme generation.
inter-coder agreement, and inconsistent results will be reviewed by the coders until consensus is reached and then codes will be grouped together into themes through consensus among coders [57,58] . We have extensive experience with in-depth interviews with purposefully sampled individuals and couples; for couples we have found dyadic interviews to be a powerful tool to explore joint decision-making and power/gender dynamics [49] . Analyses of the qualitative data will assess how both individuals and dyads respond to HIV-1 self-testing in the context of PrEP, with areas of focus such as gender roles, sexual negotiation, trust, and power. In addition, we will probe delivery, including preference of quarterly versus 6-monthly visit schedule, confidence in HIV-1 self-testing, confidence in blood versus oral fluid, and confidence in HIV-1 testing and PrEP more broadly.

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The protocol, informed consent forms (for cohort participation and for interviews of providers), and patient 1102 education and recruitment materials will be reviewed and approved by the institutional review boards at the 1103 University of Washington and at KEMRI. All participants will provide written informed consent before 1104 participation in the quantitative and qualitative interviews. Participants will be informed the purpose of the study, 1105 the procedures to be followed and the risks and benefits of participation. The consents forms will be translated into Kiswahili. Specifically the participants will be informed that this novel study will answer a critical questions on acceptability, performance and barriers of HIV-1 self testing in the context of implementation of PrEP. Participants will also be informed that the counselors may conduct a home visit to provide additional support after a positive test 1109 result if required.

1111
Study oversight

1113
This study will be subject to oversight by an independent data monitoring committee that will periodically review 1114 data from the study, including study execution, adherence, HIV-1 incidence, HIV-1 drug resistance, and serious 1115 adverse events. Review will be in an unblinded fashion, consistent with the open-label, randomized, unblinded part of six-monthly reviews. Reports from all reviews will be provided for submission to overseeing IRBs/ECs.

1119
Risks 1120 1121 Partner participants may feel pain or discomfort from phlebotomy if selected for a blood sample archive.
We have trained counselors who are available through the study to help participants deal with any feelings or 1124 questions they may have. The study staff will make every effort to protect participant privacy and confidentiality 1125 while you are in the study. However it is possible that participants' involvement in the study could become known to 1126 others, and that social harms may result (i.e., because participants could become known as participating in a trial 1127 involving HIV-1 infected persons). For example, participants could be treated unfairly or discriminated against, or 1128 could have problems being accepted by their families and/or communities.

1130
Benefits 1131 1132 Participants will benefit from ongoing access to this prevention package.

1134
This study aims to provide HIV-1 prevention policy makers with information on how to best implement antiretroviral-based HIV-1 prevention. In addition to the provision of this biomedical method, the study site will provide CHCT, and routine adherence counseling. The outcome of the study will be evidence upon which to based policy guidelines for scaling up HIV-1 prevention centers in Kenya and nearby countries with similar HIV-1 prevention needs. The HIV-1 treatment centers that serve as sites for this study will be models upon which future 1139 centers can be based. Summary outcomes from this study will be submitted to overseeing regulatory bodies and will 1140 be especially important for the development of normative guidance.

1142 1143
Care for persons identified as HIV-1 infected

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This study will identify persons who are infected with HIV-1, either as part of the study screening process or during 1146 follow-up of enrolled participants. Study staff will provide participants with their HIV-1 test results in the context of 1147 post-test counseling. Persons identified as HIV-1 infected will be referred for care.

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Treatment for injury

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Participants will be asked to inform the clinic staff if they feel they have been injured because of taking part in the 1153 study. Injuries may also be identified during laboratory testing, medical histories, and physical examinations.

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Treatment for adverse events related to study participation will be provided by the treatment clinic. If treatment is 1155 required that is beyond the capacity of the clinic, the clinic staff will refer the participant to appropriate services or 1156 organizations that can provide care for the injury.

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Implementation investigators will maintain, and store in a secure manner, complete, accurate, and current study 1161 records throughout the study. Study records include administrative documentation and regulatory documentation as

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Thika site will use a biometric system (fingerprint scanner) to identify participants during follow-up visits.

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Participants will be offered an informed consent form with the option to accept or decline to have their fingerprint 1169 taken. Participants who decline to have their finger print taken will not be excluded from taking part in the study.

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The finger print database will be destroyed after completion of active follow-up in the study.

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Every effort will be made to protect participant privacy and confidentiality to the extent possible. Personal 1175 identifying information will be retained at the local study site

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Dissemination Plan

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The study team for this award is committed to public dissemination of results of clinical trial, to trial participants, 1180 local stakeholders in Kenya, the global scientific community, and US, Kenyan, and global policymakers.

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Dissemination of study results will follow principles of good participatory practice. The clinical trial will be 1182 registered with Clinicaltrials.gov prior to initiation and results will be updated there in a timely fashion. Results will 1183 be published in conference abstracts and peer-reviewed journals. Study results will be disseminated through

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This document (Statistical Analysis Plan, SAP) describes the planned analysis and reporting for the HIV self-testing 58 to improve the efficiency of PrEP delivery (i.e., JiPime-JiPrEP) study, a joint collaboration between the objective: visits for PrEP while resulting in equivalent adherence and HIV testing.

Secondary objectives:
We will test whether the use of HIV-1 self-testing affects recent abuse by a sexual partner, the prevalence of depression, participants' self-efficacy, HIV-1 risk-related sexual behaviors, PrEP disclosure, and HIV testing preferences, compared to standard-of-care PrEP delivery (a 3-month PrEP drug supply).

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The primary objective will be tested using three primary outcomes: 1) HIV-1 testing, 2) persistence in refilling PrEP adherence 1 : Adherence to PrEP will be measured by concentrations of tenofovir diphosphate (TFV-DP) in a 3 mm punch from a dried blood spot by liquid chromatography tandem mass spectrometry (LC-MS/MS) at the participant's 6-month visit. We will measure PrEP adherence using DBS samples in two ways:  [Primary]: Any detection of TFV-DP (above the limit of quantification) (binary outcome = yes/no, denominator = all randomized subjects, missing = not detected)  [Secondary]: Concentration of TFV-DP ≥700 fmol (binary outcome = yes/no, denominator = all randomized subjects, missing = not detected) 123 1 We will measure these outcome for both the as-assigned" retention and "on-time" 6-month retention windows 124 (described above) and assume missing = fail.

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We will additionally test whether, compared to SOC PrEP delivery (a 3-month PrEP drug supply), the delivery of a 129 6-month PrEP drug supply + HIVST affects the primary outcomes (described above) when evaluated at 12 months.

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We will also measure the effect of the interventions on other secondary outcomes, including: recent abuse by a 131 sexual partner, the prevalence of depression, participants' self-efficacy, HIV risk-related sexual behaviors, PrEP 132 disclosure, and HIV testing preferences at 6 and 12 months.

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For the secondary outcomes that are the same as the primary (e.g., HIV-1 testing, persistence in refilling PrEP, and and assume missing = failure. For the secondary outcomes that are unique from the primary outcomes, we will use 137 both 6-and 12-month measurements and will not restrict any analyses to the 'on time' windows and will not impute 138 missing values as failures.

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If PrEP is discontinued by the treating clinician for safety reasons (but not adherence reasons), follow-up thereafter 141 will be censored, since the subject will not be able to be assessed for adherence to PrEP.

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HIV-1 testing 1 : 1. Any self-reported HIV-1 testing (in-clinic tests and home tests, if applicable), past 6 months 2. Two or more self-reports of HIV-1 testing between the enrollment and 12-month visit (binary outcomes = yes/no, denominator = all randomized subjects, missing = no). Persistence in refilling PrEP 1 : 1. The proportion of enrolled participants that return to the clinic and refill their PrEP medication, measured using clinic electronic dispensing data, at their 12month visit. 2. The proportion of enrolled participants that return to the clinic and refill their PrEP medication, measured using clinic electronic dispensing data, at both their 6-and 12-month visits. (binary outcomes = refilled/not refilled, denominator = all randomized subjects, missing = not refilled) PrEP adherence 1 : [See definition in primary outcomes sub-section] HIV-1 incidence: The proportion of participants (binary outcome) that test HIV-1 positive since trial enrollment (we expect this to be very low due to our small sample size, especially considering that all participants are prescribed PrEP). We will assess prevalence of genotypic HIV-1 drug resistance among any seroconverters.

Recent abuse, by sexual partner:
The proportion of participants (binary outcome) that self-report verbal, physical, or emotional abuse by a sexual partner.

Prevalence of depression:
The proportion of participants (binary outcome) that report depressive symptoms. Determined using the Patient Health Questionnaire-9 item (PHQ-9) depression scale. A 0-27 point scale where scores 10 or greater can be categorized as likely depression.

Self-efficacy:
Measured using the General Self-Efficacy Scale (GSE), which is correlated to emotion, optimism, work satisfaction, to measure self-efficacy. The scale ranges from 10-40 points -higher scores indicate more self-efficacy (continuous outcome).

Number of sexual partners:
Self-reported number of sexual partners in the past month (numeric outcome).

Inconsistent condom use:
Measured by asking participants how many times they had sex in the past month and how many times a condom was used. If condoms were not used every time, condom use was categorized as inconsistent (binary outcome). PrEP disclosure: The proportion of participants (binary outcome) that report that at least one other person (besides one's main sexual partner in serodiscordant couples) is aware they are taking PrEP.

HIV-1 testing preferences:
Participants report their preference for HIV testing from the following options: bloodbased HIV-1 self-testing, oral-fluid HIV-1 self-testing, and HIV testing at a standard health care clinic (categorical outcome).

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1 These outcomes (same as the primary, but measured at 12 months) will be measured at 12 months only.

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Primary analyses: The trial will be powered for the primary adherence outcome (measured using any detection of 151 TFV-DP in dried blood spots) at 6 months. Based on our prior work in HIV-1 serodiscordant couples and women at 152 HIV risk, we estimate ~80% among those seeking to initiate PrEP will achieve blood levels consistent with high 153 PrEP adherence. Thus, if PrEP adherence is 80% in both the standard of care and self-testing arms, with 10% loss-154 to-follow-up, a one-sided 95% confidence interval (common for non-inferiority trials), and a 10% non-inferiority 163 women at risk). The sub-analyses in serodiscordant couples and in all women will have 80% power to rule out a 164 12% decrease in PrEP adherence (i.e., a slightly greater non-inferiority margin).

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We recognize that women outside of serodiscordant couples (N=200) may face unique adherence challenges and 167 less frequent follow-up could be truly inferior to quarterly follow-up; thus, we also plan a superiority analysis for 168 these women. In this analysis, we will have 80% power to detect a decline in PrEP adherence from 80% to 66% 169 (14% lower) with self-testing.

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Primary analyses: The primary adherence analysis has been redesigned to impute those LTFU as nonadherent, so 174 that all participants randomized will contribute to the analysis. With a 10% non-inferiority margin, if PrEP 175 adherence is 80% in both the standard of care and self-testing arms, our total sample size of N=495 will provide 176 83.6% power to rule out a greater than 10% decrease in adherence. However, counting those missing as nonadherent 177 will likely lead to <80% considered adherent. If 70% are adherent in each arm, we will have 74% power to rule out 178 more than a 10% difference. While power <80% is not ideal, the trade-off of including all participants in the analysis is an important consideration in this implementation science study. analysis in the entire study population: if we assume PrEP adherence is 80% in SOC, to rule out a 10% decrease in opaque randomization envelope, given to them by a study pharmacist, that has their study arm assignment inside.

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This study is unmasked. To minimized implementation bias, we have implemented procedures that standardize 214 participant contact across the study arms:

12-month*
DO NOT contact participants because they do not have a scheduled visit Standard clinical procedures for reminding individuals of their appointment: Call one day after missed scheduled visit date then repeat seven days after the first call. An alternative contact, as listed in the locator form, will be called during the second week (after the repeat call made 7 days after the first attempt to contacting participant) if participant fails to answer phone calls from the clinic. *At 12-months, if participants do not returned for their scheduled clinic visit after standard contact procedures have been implemented and 3 months have passed, we will note this and engage in more intensive efforts to follow-up with this participants (including home visits) so that we can collect end-line data (including a DBS sample) from participants.

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All quantitative data will be collected electronically in face-to-face interviews with trained Thika HIV-1 counselors, 221 clinicians, and pharmacists. We will use CommCare (Dimagi, Cambridge, USA), an electronic data collection 222 platform, to collect the quantitative data and will upload this data to CommCare's secure server daily. A team of 223 data experts in both Thika and Seattle will monitor the data as it is coming in, and Seattle team will generate weekly 224 data quality reports that will be shared with the Thika team for review and feedback.

53
Thika site code 18 Protocol number XXX Sequential digits, specific to participant groups:

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For all primary outcomes (e.g., HIV-1 testing, persistence in PrEP refilling, and PrEP adherence) we will assume 235 that missing equals failure; for participants not retained in the relevant 6-month (or 12-month) retention windows 236 described in section 4.1.1, the response will be considered missing (and therefore failure). As a potential sensitivity 237 analysis, we may impute missing outcomes using information gleaned through extensive follow-up of participants 238 who miss their 12-month PrEP visit and phone-based surveys conducted during the periods of COVID-19 lockdown,

239
and controlling for potential confounders in our analyses.

243
An alpha of 0.05 will be used for the primary analyses and pre-specified secondary analyses. For pre-specified secondary analyses, we will report both the p-value and the number of pre-specified analyses performed.

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Data sets. Data sets for analysis will be produced by Katrina Ortblad, Dorothy Mangale, and Ashley Bardon. They 249 will be .dta or .csv files containing a single header line whose variable names match those coded in CommCare. All 250 missing values will be coded using "999". Codes for categorical variables (e.g., 0 for "No" and 1 for "Yes") will be 251 used instead of character strings whenever possible.

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Data codebook. A detailed codebook will be prepared, containing for each variable the form from which the variable 254 derived, the text of the question, and all possible values for that variable with their coding. All codes and character 255 strings representing categorical factors will be defined in the codebook.

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The study will be monitored by a Data Scientific and Monitoring Board (DSMB) approximately every six months.

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The project director and statistician will generate both an open and closed report (statistician only) that will be 260 shared with the DSMB prior to the meeting. The DSMB will give recommendations based on the report and 261 accompanying presentation, and all recommendations and meeting minutes will be reported to the UW and Kenyan

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Analyses. All analyses comparing randomization arms will be by intention-to-treat. The primary comparison will be 268 self-testing versus clinic testing; the two self-testing modalities will be analyzed together (versus SOC in-clinic 269 testing) because we hypothesize that the effect on adherence and other outcomes relates to the use of self-tests and 270 frequency of follow-up, not the self-test modality.

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Model adjustments. Models comparing randomized arms will include study arm as the primary predictor in the 272 model, and will adjust only for study population (male in partnership, female in partnership, or female not within 273 partnership). Supplemental, adjusted analyses also will be performed where potential confounders are found to differ 274 at baseline. Potential confounders considered will be based on our prior work assessing correlates of PrEP use: 275 demographics (e.g., gender, age, educational level), sexual behaviors (e.g., condom use, outside partnerships), 276 medical status (e.g., depression), and beliefs (e.g., risk perception, PrEP efficacy). Models containing more than one 277 time point (e.g., 6 month and 12 month data in one analysis) will adjust for time point.

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Significance. Significance will be assessed using a two-tailed test at the 0.05 level.

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Baseline characteristics will be described by study arm and study population. These will include demographic 283 variables, HIV-1 testing history, sexual behaviors, and history of intimate partner violence.

Analysis of primary objective outcomes
PrEP adherence (any detection of TFV-DP in DBS samples) at 6 months. At 6 months, we will measure these 290 outcomes using two different retention windows: 1) "as-assigned" retention and 2) "on-time" retention. If 291 participants are not retained in care (i.e., the outcome is missing when visit is restricted to the specific retention 292 window), then we will impute the outcome as described in section 4.1, describing primary endpoints.

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The proportion of participants with each outcome in each of the retention windows will be described by randomized 295 group. Our hypothesis is that the combined HIVST groups will be non-inferior to the SOC group for each of the 296 specified primary objective outcomes. Statistical comparison will be a one-sided non-inferiority comparison, using a 297 binomial regression model with identity link to estimate the risk difference (RD) for the outcome in the HIVST arm 298 compared to SOC. If we encounter problems with model convergence, we will instead use a linear regression model 299 (Gaussian errors and identity link) modified with robust standard errors to allow valid inference in the context of 300 misspecification of the error structure as Gaussian rather than binomial. If the one-sided 95% CI for the RD (HIVST

301
-SOC) excludes values below -10%, then the results will be interpreted as showing that the HIVST groups were 302 non-inferior to SOC. If the 95% CI includes values below -10%, then HIVST is not non-inferior. We will test 303 different retention windows in various sensitivity analyses, including a sensitivity analysis where outcomes are not 390 All serious and non-serious adverse events will be included in interim and final monitoring reports.

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A summary of changes that have been made to the SAP after unblinding is presented below. All changes are in bold. Page 14 of 18 (Section 10.4, Analysis of secondary outcome variables) was updated to indicate that risk differences will be presented for the secondary analysis outcome variables instead of relative risks and that the effect size for each secondary outcome variable would be estimated at two timepoints: months 6 and 12.

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We also clarified that 95% CIs for these outcomes will be two sided.
We have revised the effect size estimates for secondary variables to present risk differences to be consistent with the primary outcome estimates. We have also revised the analyses to estimate separate effect sizes for months 6 and 12, as we predict that the outcomes at these timepoints are not correlated and will actually be different. Kenyan guidelines recommend that people in serodifferent partnerships discontinue PrEP after their HIVpositive partner has been on ART for at least 6 months. Therefore, we predict that many people will discontinue PrEP for this reason by month 6, and outcomes at month 12 will likely be different. Additionally, we have clarified that the 95% confidence intervals for these effect size estimates will be two-sided, as these analyses are not intended to establish noninferiority of the intervention as our primary outcome comparison does. Page 7 of 18 (Section 4.2, Secondary outcomes) was revised to update the definition of PrEP adherence at 12 months for participants in an HIV-1 serodiscordant couple. These participants will not be counted as adherent to PrEP at 12 months if they discontinue PrEP because their HIV-positive partner has initiated and sustained ART for >6 months.
We have revised the secondary outcome definition for PrEP adherence at 12 months, as we do not anticipate that the intervention will have an effect on HIV-positive partners' ART adherence; therefore, we anticipate PrEP discontinuation due to this reason will be equally distributed across study arms since the number of participants in HIV serodiscordant partnerships is the same for each study arm. Instead, we will discuss the potential limitations of our analyses when we present the findings, and we have added a subgroup analysis and a sensitivity analysis to better understand the effect of the intervention on PrEP discontinuation. Page 15 of 18 (Section 10.5, Sub-group analyses) was updated to include an additional exploratory analysis among participants in HIV-1 serodiscordant couples who continue to be at risk for HIV acquisition at 12 months.
In this subgroup analysis, we will exclude singly enrolled women and participants who discontinue PrEP at 12 months due to no longer being in an HIV-1 serodiscordant partnership or if their partner has sustained ART for >6 months or achieved viral suppression. This analysis will evaluate the true association between the intervention and PrEP refilling and adherence by removing the effects of partners' behaviors on HIV risk.

Page 15 of 18 (Section 10.6, Sensitivity
This sensitivity analysis was added to analysis) was updated to include a sensitivity analysis among HIV-1 serodiscordant couples in which all secondary outcomes at 12 months among those who have discontinued PrEP following Kenya guidelines (i.e., due to no longer being in an HIV-1 serodiscordant partnership or if their partner has sustained ART for >6 months or achieved viral suppression) will be classified as having been achieved.
determine if the effects of the intervention change when discontinuing PrEP due to a reduction in HIV risk is also counted as a success.
12 Jan 2022: Version 4.1 to version 4.2 Page 7 of 18 (Section 4.2. Secondary outcomes) was revised to change the definition of the secondary outcome of 'persistence in refilling PrEP at 12 months' to reflect the same measure at 6 months. The definition was changed from 2 outcome measures: (1) Any PrEP refill in past 6 months and (2) Two or more PrEP refills between enrollment and 12-month visit.
We've changed the definition of this measure back to the definition of the variable from an earlier version of the SAP, which was the correct definition. We have also added an additional outcome measure to determine the persistence in PrEP refilling at both 6-and 12month visits.
28 Mar 2022: Version 4.2 to version 4.3 Page 14 of 18 (Section 10.4. Analysis of secondary outcome variables) was revised to also report means for each continuous outcome and to remove the language about mixed linear regression models.
We have fixed two errors that were discovered for the analyses of continuous outcomes.